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Many of us, in childhood, enjoyed a game called Capture the Flag. With much strategizing, hiding and running, two teams of many players attempt to capture the other team’s flag and bring it back victoriously to their side without being tagged. During this showdown, players try to tag as many players from the other team as possible and bring them to “prison,” thus decreasing the number of adversaries.

In a busy lab at St. Jude Children’s Research Hospital, Brenda Schulman, PhD, and a group of her Structural Biology colleagues are studying their own version of Capture the Flag, learning how “adversaries” in cells are tagged and brought to a prison where they are then disposed of.

Tag, you’re out

Even as a kid smitten with blocks, shapes and math puzzles, Schulman was fascinated by how things fit and work together—specifically, how cells in the body could respond to changing environmental demands and cues.

A cell in a person’s body is like, let’s say, the field on which a game of Capture the Flag is being played. On that cell, players can sneak around wreaking havoc for the other team. Like a playing field, a cell can contain unneeded or abnormal material that can cause illness or even death. Some materials in the cell have important jobs that must be done at specific times and then must be eliminated once the tasks are completed. Fortunately, cells have an ingenious process to get rid of this unwanted material.

Each cell contains a protein called ubiquitin, which consists of 76 amino acids. These 76 players roam the cell, tagging unwanted or waste material. Like captured players escorted to the other team’s prison, the tagged material is brought to a waste area, called the proteasome, where it is chopped up into bits or degraded. This waste-disposal system is called the ubiquitin-proteasome system because ubiquitin recognizes damaged, incorrectly assembled or otherwise unwanted proteins and tags them for destruction.

This research is no game; further discoveries about the process may help lead to treatments for cancer, Parkinson’s, Alzheimer’s and other diseases.

Capture the ubiquitin

“Most of the processes we study are controlled by proteins that are built up and broken down at a frenetic rate,” Schulman says. The cell must turn on and off a variety of biochemical pathways that serve thousands of critical functions, ranging from cell division and brain development in a baby to immune responses. The cell regulates these pathways to maintain conditions conducive to its own health and ability to perform its assigned function.

“We’re still trying to figure out what these proteins do normally in the first place so that when there’s a defect in the patient’s cellular make-up, we will know what has gone wrong on that level,” Schulman says. “The pathway we’re studying is fundamental to human cellular regulation.”

By studying the 3-D structure of proteins participating in the “Capture the Ubiquitin” game, Schulman and her team can better understand how cells keep their biochemical pathways operating in an orderly way, and how their disruption can lead to disease. The investigators are especially interested in how this process controls the levels of molecules that drive cell division, because cancer can develop if these molecules are not tagged and disposed of at the appropriate time. With further research, investigators could provide drug makers with crucial information on how to target molecules that fail to get tagged.

Schulman and her team use X-ray crystallography to study the protein structures and how they bind to one another. After purifying proteins, the researchers grow microscopic crystals that look like the sugar crystals on a stick you might get with a cappuccino at a fancy café. Once grown, the crystals are shipped to one of a handful of national laboratories, such as the Advanced Photon Source at Argonne National Laboratory in Illinois; there, the crystals are bombarded by huge X-ray beams. These X-rays show diffraction patterns from which computer-generated, 3-D images are created. From those images, Schulman and her team can figure out how specific proteins in the ubiquitination pathway bind to each other and in what combinations, thus revealing the nature and sequence of biological pathways.

“Research like mine is not for the impatient,” Schulman explains. “You just have to jump and hope there is water in the pool at the bottom. I mean, I can see the water in the pool; it’s there, I just don’t know how long the jump will be.”

And the game goes on

Working at St. Jude has already helped Schulman take giant steps in her work. “This is a very collaborative environment,” she says.” We work with many other labs and researchers; we share what we are doing—our ideas, our questions. I’m excited about being able to pursue these adventurous projects.”

Since arriving at St. Jude more than four years ago, Schulman has been selected as a Pew Scholar, a Howard Hughes Medical Institute investigator and a Presidential Early Career Award for Scientists and Engineers recipient. Schulman admits that her work is her passion, consuming most of her time and thought.

“Many mornings, I have one or two or several messages on my St. Jude voice mail from myself calling in the middle of the night,” she says. Instead of writing down an idea or thought, she dials her work number. In the morning, the red light on her phone blinks impatiently with her nighttime brainstorms.